{"gene":"IL17RA","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2008,"finding":"IL-25 (IL-17E) signaling requires both IL-17RB and IL-17RA subunits to form a functional heteromeric receptor complex; knockout of either subunit or antibody blockade of either receptor abolishes IL-25-induced IL-5/IL-13 production and pulmonary inflammation in vivo.","method":"Knockout mice (IL-17RB KO and IL-17RA KO), antagonistic monoclonal antibodies, in vitro splenocyte assays, intranasal IL-25 challenge model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal KO + antibody blockade, replicated across in vitro and in vivo systems in same study","pmids":["18768888"],"is_preprint":false},{"year":2008,"finding":"The IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex; IL-17RA binds IL-17A with higher affinity than IL-17F or the heterodimer (measured by surface plasmon resonance), while IL-17RC binds all three cytokines with comparable affinity; soluble IL-17RA preferentially neutralizes IL-17A activity.","method":"siRNA knockdown of IL-17RA and IL-17RC, surface plasmon resonance (binding affinity), soluble receptor neutralization assays, bronchial epithelial cell cytokine secretion assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — biophysical binding measurements + functional siRNA knockdown + soluble receptor assays, multiple orthogonal methods","pmids":["18684971"],"is_preprint":false},{"year":2008,"finding":"Both IL-17RA and IL-17RC are required for IL-17A-induced ELR+ CXC chemokine (IL-6, IL-8, CCL-20) expression in synoviocytes; siRNA silencing of either receptor abrogates IL-17A-mediated signaling, and combined inhibition is required when TNF-α is also present.","method":"siRNA knockdown of IL-17RA and IL-17RC in rheumatoid arthritis synoviocytes, ELISA, microarray gene expression analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — siRNA knockdown with defined cytokine readouts, multiple orthogonal methods","pmids":["18097068"],"is_preprint":false},{"year":2010,"finding":"IL-17RA-mediated signaling requires an extended C-terminal domain beyond the previously identified SEFIR motif; Act1 recruitment to IL-17RA is necessary but not sufficient for downstream signaling, whereas TRAF6 ubiquitination correlates tightly with functional receptor activity. IL-17RA signals synergistically with lymphotoxin-α3 using the same signaling motifs.","method":"Structure-function mutagenesis of IL-17RA C-terminal domain, Act1 recruitment assays, TRAF6 ubiquitination assays, cell-based signaling readouts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — detailed mutagenesis with multiple functional readouts in same study","pmids":["20729198"],"is_preprint":false},{"year":2011,"finding":"The CC' loop of the SEFIR domain of Act1 directly mediates interaction with IL-17RA; a cell-permeable decoy peptide based on the CC' loop sequence inhibits IL-17- and IL-25-mediated signaling in vitro and pulmonary inflammation in vivo. Deletion of the BB' loop (unlike in TIR domains) does not affect Act1-IL-17RA interaction.","method":"Domain deletion mutagenesis, surface plasmon resonance (direct binding of CC' loop peptide to IL-17RA), cell-permeable peptide in vitro and in vivo inhibition, pulmonary inflammation mouse model","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 — direct biophysical binding + mutagenesis + in vivo functional validation, multiple orthogonal approaches","pmids":["22045852"],"is_preprint":false},{"year":2011,"finding":"IL-17RA signaling is required for CCL2 and MMP12 expression and macrophage recruitment in the lung in response to cigarette smoke; IL-17RA-deficient mice fail to develop emphysema after 6 months of cigarette smoke exposure.","method":"IL-17RA knockout mice, cigarette smoke exposure model, qPCR for CCL2/MMP12, histological assessment of emphysema","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular and molecular phenotypes, in vivo model","pmids":["21647421"],"is_preprint":false},{"year":2012,"finding":"IL-17RA signaling amplifies inflammatory arthritis by directly activating synovial fibroblasts to produce multiple pro-inflammatory mediators (CXCL1, CXCL2, CXCL5, IL-1β, IL-6, RANKL, MMP2, MMP3, MMP13); IL-17RA-deficient mice show reduced cartilage and bone erosions in the K/BxN serum-transfer arthritis model.","method":"IL-17RA knockout mice in K/BxN serum-transfer arthritis model, qPCR for cytokines/chemokines, in vitro IL-17A stimulation of synovial fibroblasts, histological bone/cartilage assessment","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — KO model with defined molecular phenotypes confirmed by in vitro fibroblast studies","pmids":["22028860"],"is_preprint":false},{"year":2012,"finding":"IL-17RA signaling in the aortic vasculature promotes atherosclerotic plaque formation by inducing aortic chemokines (TNFα, CXCL2) and supporting monocyte/neutrophil adherence and recruitment to the aortic arch; IL-17RA-deficient Apoe-/- mice show reduced aortic arch atherosclerosis.","method":"IL-17RA-/- x Apoe-/- double-knockout mice, Western diet feeding, flow cytometry, ex vivo monocyte adhesion assays, short-term adoptive transfer homing experiments","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — KO model with multiple orthogonal assays including ex vivo adhesion and adoptive transfer","pmids":["22302786"],"is_preprint":false},{"year":2013,"finding":"IL-17RA expressed on follicular T helper (TFH) cells is required for their localization to the germinal center light zone and interaction with B cells; IL-17 upregulates RGS16 in TFH cells to promote TFH-B cell conjugate formation, leading to autoantibody-producing B cell generation in BXD2 mice.","method":"BXD2-Il17ra-/- mice, conditional IL-17R:Fc blockade, confocal microscopy of GC light zone localization, in vitro B cell response assays, RGS16 expression analysis, BXD2-Rgs16-/- mice","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO + blocking experiments + defined molecular mechanism (RGS16), confirmed by additional KO line","pmids":["23858031"],"is_preprint":false},{"year":2016,"finding":"Inherited autosomal recessive IL-17RA deficiency in humans abolishes cellular responses to IL-17A, IL-17F homodimers, IL-17A/F heterodimers (in fibroblasts), and IL-17E/IL-25 (in leukocytes), establishing IL-17RA as essential for mucocutaneous immunity to Candida and Staphylococcus.","method":"Primary fibroblast and leukocyte functional assays from 21 patients with defined IL-17RA loss-of-function mutations; surface expression of 12 different IL-17RA alleles characterized","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — direct functional cellular assays in primary patient cells with multiple defined loss-of-function alleles, replicated across 21 patients","pmids":["27930337"],"is_preprint":false},{"year":2017,"finding":"Cyanidin specifically binds to an IL-17A-binding site on IL-17RA, blocking the IL-17A/IL-17RA protein-protein interaction; this inhibits IL-17A-induced skin hyperplasia and TH17-mediated airway inflammation in vivo.","method":"Structure-based virtual screening, molecular binding assays, murine skin hyperplasia model, murine asthma models, selectivity testing against TH1/TH2-mediated inflammation","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 — structure-based identification + multiple in vivo mechanistic validation models","pmids":["28223414"],"is_preprint":false},{"year":2018,"finding":"RKIP (Raf-1 kinase inhibitor protein) directly interacts with both IL-17RA and Act1 to promote formation of the IL-17R-Act1 signaling complex, resulting in enhanced MAPK and NF-κB activation and downstream inflammatory cytokine production; RKIP deficiency ameliorates experimental autoimmune encephalomyelitis (EAE) by impeding Th17- but not Th1-mediated responses.","method":"Co-immunoprecipitation of RKIP with IL-17RA and Act1, adoptive T-cell transfer (Th17 vs Th1), RKIP-deficient mice in EAE model, cytokine/chemokine production assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — direct Co-IP showing complex formation + KO with defined mechanistic pathway + adoptive transfer selectivity","pmids":["29674348"],"is_preprint":false},{"year":2019,"finding":"IL-17A recruits Rab35 (and its GEF DennD1C) to the IL-17R/Act1 complex in airway smooth muscle cells, activating Rab35 to promote PKCα activation and fascin phosphorylation at Ser39, allowing F-actin/myosin stress fiber formation and enhanced airway smooth muscle contraction.","method":"Cell type-specific IL-17R/Act1 deletion, Co-IP of Rab35/DennD1C with IL-17R/Act1 complex, Rab35 knockdown, PKCα inhibitor, immunofluorescence for stress fibers, airway smooth muscle contraction assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP of complex + conditional deletion + multiple mechanistic steps validated with inhibitors and knockdown","pmids":["30683702"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of the extracellular domain of IL-17RC in complex with IL-17F reveals that IL-17RC forms a symmetrical 2:1 complex with IL-17F, competing with IL-17RA for cytokine binding; IL-17A and IL-17A/F heterodimer also form 2:1 complexes with IL-17RC, demonstrating the structural basis for potential IL-17RA-independent signaling.","method":"X-ray crystallography of IL-17RC:IL-17F complex, biophysical techniques to characterize IL-17A and IL-17A/F complexes with IL-17RC","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 — crystal structure determination with biophysical validation","pmids":["32187518"],"is_preprint":false},{"year":2022,"finding":"IL-17A, IL-17F, and IL-17A/F induce IL-17RA dimerization; X-ray crystallography of the heteromeric IL-17A complex with extracellular domains of IL-17RA and IL-17RC reveals a 2:2:2 hexameric signaling assembly (signalosome); formation of this signalosome potentiates IL-17-induced IL-36γ and CXCL1 expression in human keratinocytes compared to a dimerization-defective IL-17RA variant.","method":"X-ray crystallography, biophysical binding studies, mutagenesis of IL-17RA dimerization interface, keratinocyte gene expression assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — crystal structure + mutagenesis + functional validation in primary cells","pmids":["36260993"],"is_preprint":false},{"year":2022,"finding":"IL-17RA signaling in Lgr5+ intestinal stem cells induces ATOH1 transcription factor expression to promote secretory cell lineage commitment (Paneth, tuft, goblet, enteroendocrine cells); IL-17RA signaling in ATOH1+ cells is required to regenerate secretory cells following injury; IL-17A stimulation of human intestinal organoids rescues secretory cell differentiation.","method":"Multiple conditional deletion models (Lgr5-Cre, ATOH1-Cre), intestinal injury models, human intestinal organoid stimulation, lineage tracing, cell counting","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — multiple conditional KO models + organoid functional validation + defined transcription factor mechanism","pmids":["35081371"],"is_preprint":false},{"year":2022,"finding":"FTO (fat mass and obesity-associated RNA demethylase) reduces m6A methylation of IL-17RA mRNA in liver tissue, increasing IL-17RA expression and promoting chronic hepatic inflammation; knockdown and overexpression of FTO in vitro and in vivo confirm FTO as the main modulator of IL-17RA m6A levels.","method":"MeRIP-seq on human liver tissues, FTO knockdown/overexpression in vitro and in vivo, NAFLD and chronic liver injury mouse models, comparison with METTL3, METTL14, ALKBH5","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 — MeRIP-seq + KD/OE functional validation, single lab but orthogonal in vitro/in vivo approach","pmids":["36172147"],"is_preprint":false},{"year":2019,"finding":"IL-17A signals through the IL-17A/IL-17RA/p-STAT3/FABP4 axis in ovarian cancer cells to promote fatty acid uptake and cancer cell proliferation in an adipocyte-rich microenvironment; this is dependent on IL-17RA but not CD36.","method":"In vitro palmitic acid uptake assays with IL-17A stimulation, IL-17RA pathway analysis, orthotopic implantation model in IL-17A-deficient mice, FABP4 and p-STAT3 expression analysis","journal":"Cancer immunology, immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro mechanistic pathway + in vivo KO model, single lab","pmids":["31802182"],"is_preprint":false},{"year":2010,"finding":"IL-17A and IL-17F both signal through IL-17RA and IL-17RC in rheumatoid synoviocytes activating NF-κB and MAPKs; siRNA silencing of either receptor nearly completely abrogates IL-17A-mediated IL-6 expression and IL-17F+TNF-α-mediated responses; IL-17A activates ERK, p38, JNK and induces TRAF6 but not MyD88.","method":"Affymetrix microarrays, ELISA, siRNA knockdown of IL-17RA/RC, Western blotting, NF-κB and AP-1 DNA binding assays","journal":"Annals of the rheumatic diseases","confidence":"High","confidence_rationale":"Tier 2 — siRNA + multiple signaling readouts, orthogonal approaches","pmids":["21109515"],"is_preprint":false},{"year":2013,"finding":"A soluble isoform of human IL-17RA is generated by alternative splicing (exclusion of exon 11 encoding the transmembrane region) and is secreted into cell culture media, providing a potential endogenous regulator of IL-17RA-mediated responses.","method":"RT-PCR in human tissues, Western blotting of culture media to detect soluble isoform protein","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 — molecular characterization at mRNA and protein level, but functional consequences not directly measured","pmids":["24084331"],"is_preprint":false},{"year":2019,"finding":"IL-17RA signaling in intestinal epithelial cells regulates the microbiome and constrains bacterial product (CpG DNA) translocation to the liver; absence of intestinal epithelial IL-17RA leads to microbiome dysbiosis, increased hepatic IL-18 production, and exacerbated immune-driven hepatitis.","method":"Intestinal epithelium-specific IL-17RA-deficient mice (conditional KO), immune-driven hepatitis model, microbiome analysis, bacterial product translocation assays, IL-18 measurement","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific conditional KO with defined mechanistic pathway linking intestinal IL-17RA to liver disease via microbiome","pmids":["31747600"],"is_preprint":false},{"year":2019,"finding":"IL-17RA signaling in non-hematopoietic lung fibroblasts (rather than hematopoietic cells) is required for vaccine-elicited TH17-mediated lung-specific immunity to Klebsiella pneumoniae, acting through STAT3 expression.","method":"Fibroblast-specific IL-17RA deletion, STAT3-deficient mice, adoptive transfer of vaccine-elicited CD4+ T cells, lung-specific immunity readouts","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — cell-type specific conditional deletion identifying fibroblast IL-17RA as the functional signal transducer","pmids":["34516780"],"is_preprint":false},{"year":2016,"finding":"IL-17RA expressed on non-hematopoietic (structural) lung cells is required for CXCL-1 and CXCL-5 production and subsequent adaptive neutrophil recruitment during Mycobacteria infection; CXCL-1/5 instillation rescues neutrophil recruitment in IL-17RA-/- mice.","method":"IL-17RA-/- mice, BCG/Mtb intranasal infection model, bone marrow chimeras to distinguish hematopoietic vs non-hematopoietic IL-17RA, CXCL-1/5 reconstitution experiment","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — KO + bone marrow chimeras + cytokine reconstitution, multiple complementary approaches","pmids":["26871571"],"is_preprint":false},{"year":2019,"finding":"IL-17A signals through IL-17RA to activate NF-κB-mediated fibrogenic responses in lung fibroblasts (ECM production, myofibroblast transdifferentiation, proliferation); siRNA silencing of IL-17RA attenuates these responses; JAK2 (but not JAK1/3) is also required for IL-17A-induced fibrogenic responses in fibroblasts.","method":"siRNA silencing of IL-17RA in normal and IPF fibroblasts, NF-κB inhibition, JAK2 siRNA and selective pharmacological inhibitors (AZD1480 vs tofacitinib), ECM protein measurement, myofibroblast marker assays","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 — siRNA + selective pharmacological inhibitors with multiple orthogonal mechanistic readouts","pmids":["30604628"],"is_preprint":false},{"year":2019,"finding":"IL-17B signals through IL-17RA and IL-17RB receptor subunits (like IL-25/IL-17E) to induce type 2 cytokine secretion from human innate type 2 lymphocytes, NKT, and Th2 cells; IL-17B can augment IL-33-driven type 2 responses.","method":"Receptor subunit blocking antibodies and genetic dependence studies in human primary lymphocytes, cytokine secretion assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — antibody-based receptor blockade in primary human cells, single lab","pmids":["30770417"],"is_preprint":false},{"year":2025,"finding":"IL-17RA in intestinal epithelial cells (IECs) suppresses EMT via restraint of EGFR/Src signaling; in macrophages, IL-17RA is required for Syk kinase activation upon dectin-1 engagement by fungi, enabling IL-18 release and protective CD8+ T cell anti-tumor immunity in colorectal cancer.","method":"Conditional IL-17RA deletion in IECs and macrophages, CRC mouse model, EGFR/Src pathway analysis, dectin-1/Syk signaling assays, IL-18 measurement, CD8+ T cell functional readouts, combinatorial immunotherapy experiments","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific conditional KOs revealing two distinct IL-17RA signaling mechanisms in distinct cell types, multiple orthogonal readouts","pmids":["40023157"],"is_preprint":false},{"year":2016,"finding":"IL-17RA in osteoclast precursors (conditional deletion with LysM-Cre) promotes osteoclast formation and subsequent bone resorption; IL-17ra conditional KO mice display increased trabecular bone mass due to reduced osteoclast precursor abundance.","method":"LysM-Cre conditional IL-17ra knockout, microCT bone analysis, histomorphometry, in vitro osteoclast differentiation assays","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 — cell type-specific conditional KO with defined in vivo and in vitro phenotypes, single lab","pmids":["34973492"],"is_preprint":false},{"year":2024,"finding":"Gingerenone A (GA) directly binds IL-17RA protein to inhibit IL-17 signaling; lentivirus-mediated IL-17RA/Act1 knockdown or co-treatment with brodalumab/ixekizumab impairs GA's protective effects against DSS-induced colitis, confirming IL-17RA as the molecular target.","method":"Pull-down assay, surface plasmon resonance, molecular dynamics simulation, lentiviral IL-17RA/Act1 knockdown, DSS-induced colitis mouse model, brodalumab/ixekizumab co-treatment","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding confirmed by SPR + MD simulation + genetic/pharmacological loss-of-function","pmids":["38639442"],"is_preprint":false},{"year":2018,"finding":"IL-17A signaling through IL-17RA promotes MMP-2 and MMP-9 expression and NSCLC cell invasion via p38 MAPK pathway; p38 MAPK-specific inhibitor SB203580 suppresses IL-17RA-dependent migration and invasion; MMP-2/9 are downstream effectors of the IL-17RA/p38 axis.","method":"IL-17RA overexpression/knockdown in NSCLC cell lines, p38 MAPK inhibitor (SB203580), wound healing/Transwell invasion assays, Western blotting","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD/OE with pharmacological inhibitor confirming pathway, single lab","pmids":["30564960"],"is_preprint":false},{"year":2017,"finding":"IL-17 regulates Cyr61, IL-23, GM-CSF, and RANKL expression in fibroblast-like synoviocytes via an IL-17RA/STAT-3 signaling cascade; IL-17RA knockdown reverses IL-17-induced SHP-2 upregulation and abolishes the osteoclastogenic potential of IL-17-treated FLS.","method":"siRNA knockdown of IL-17RA, STAT-3 inhibitor (S3I-201), co-culture osteoclast differentiation assays, Western blotting, TRAP staining","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — siRNA + pharmacological inhibitor with multiple readouts, single lab","pmids":["28898718"],"is_preprint":false},{"year":2019,"finding":"IL-17RA/Act1 signaling is required for IL-17RA dimerization following IL-17A stimulation of airway smooth muscle cells; IL-17RA signaling also requires cell-type-specific Act1 for its direct effect on airway smooth muscle contraction.","method":"Cell type-specific deletion of IL-17R and Act1 in airway smooth muscle cells, Co-IP for complex formation","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — cell type-specific deletion with functional airway contraction readout","pmids":["30683702"],"is_preprint":false},{"year":2019,"finding":"Oxidative stress induces KLF4 transcription factor, which directly activates IL-17RA expression in retinal pigment epithelial cells, leading to IL-1β and IL-8 production; IL-17RA knockdown prevents OS-induced RPE apoptosis and inflammatory response.","method":"siRNA knockdown of IL-17RA and KLF4, promoter-binding assays, flow cytometry for apoptosis, AMD-like mouse model","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — transcriptional regulation mechanism with KD functional validation, single lab","pmids":["31881336"],"is_preprint":false},{"year":2024,"finding":"IL-17A impedes efferocytosis in synovial macrophages via preferential activation of JAK/STAT-3/ADAM17 signaling axis, causing ADAM17-mediated shedding of MERTK; disruption of IL-17A/IL-17RA interaction (by cyanidin or IL-17RA silencing) abolishes ADAM17 expression, reduces MERTK shedding, and restores efferocytosis.","method":"IL-17RA silencing, cyanidin treatment, ADAM17 knockdown, MERTK shedding assays, efferocytosis functional assays, flow cytometry for macrophage phenotype, adjuvant-induced arthritis model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic + pharmacological IL-17RA blockade with multiple mechanistic readouts, single lab","pmids":["38810305"],"is_preprint":false},{"year":2018,"finding":"IL-17RA-/- mesenchymal stem cells (MSCs) lose immunosuppressive function in experimental autoimmune encephalomyelitis; IL-17RA-/- MSCs fail to reduce Th17 cell frequency and fail to generate CD4+CD25+Foxp3+ Tregs, correlating with reduced VCAM1, ICAM1, and PD-L1 expression on MSCs.","method":"IL-17RA-/- MSCs in EAE model, adoptive transfer, flow cytometry, gene expression analysis of immunosuppressive mediators","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — KO MSCs in defined in vivo model with mechanistic readouts, single lab","pmids":["29760692"],"is_preprint":false},{"year":2005,"finding":"IL-17 receptor (IL-17RA) is expressed on human airway smooth muscle cells; IL-17 induces CXCL-8 production via transcriptional mechanisms dependent on NF-κB and AP-1 binding sites in the CXCL-8 promoter; transcriptional inhibitor actinomycin D abolishes this response.","method":"IL-17R expression by RT-PCR, Western blotting, and surface immunostaining; CXCL-8 promoter reporter assays with wild-type and site-specific mutant constructs; actinomycin D inhibition","journal":"Clinical immunology","confidence":"High","confidence_rationale":"Tier 1-2 — promoter mutagenesis + reporter assays with multiple validation methods","pmids":["15893694"],"is_preprint":false},{"year":2009,"finding":"IL-17RA signaling is required for weight loss, neutrophil migration, MPO accumulation, and oxidized phospholipid generation in the lung during influenza infection, but is dispensable for CD8+ T cell recruitment and viral clearance.","method":"IL-17RA-/- mice in influenza infection model, bronchoalveolar lavage cell counting, MPO measurement, oxidized phospholipid quantification, flow cytometric analysis of influenza-specific CD8+ T cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — KO model with multiple mechanistic dissection of IL-17RA-dependent vs -independent pathways","pmids":["19783685"],"is_preprint":false},{"year":2011,"finding":"The pre-ligand assembly domain (PLAD) of IL-17RA mediates receptor-chain associations essential for IL-17 signaling; blocking IL-17RA PLAD with an Ig fusion protein reduces myocardial collagen production (MMP-2, MMP-9, TIMP-1, -2, collagen I/III) and improves diastolic cardiac function in spontaneously hypertensive rats.","method":"Lentiviral delivery of IL-17RA PLAD-Ig in spontaneously hypertensive rats, echocardiography, immunoblotting for MMP/TIMP/collagen, collagen quantitation","journal":"Experimental and molecular pathology","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo PLAD blockade with defined molecular and functional readouts, single lab","pmids":["21530504"],"is_preprint":false},{"year":2018,"finding":"IL-17RA signaling in CD8+ T cells is intrinsically required for maintenance of functional effector CD8+ T cells during Trypanosoma cruzi infection; in vitro recombinant IL-17 downregulates pro-apoptotic protein BAD and promotes CD8+ T cell survival.","method":"IL-17RA KO mice in T. cruzi infection model, adoptive transfer experiments, intracellular BAD expression analysis, PD-L1 blockade, transcriptomic profiling","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — KO + adoptive transfer establishing cell-intrinsic requirement + defined molecular (BAD) mechanism","pmids":["30364284"],"is_preprint":false},{"year":2016,"finding":"A linear 15-residue peptide antagonist (HAP) binds IL-17A and blocks IL-17RA binding; crystal structure shows two HAP molecules bind one IL-17A dimer symmetrically, with N-terminal portions forming a β-strand inserted between IL-17A monomers and C-terminal helix directly blocking the IL-17RA binding site on IL-17A.","method":"Phage-display peptide screening, saturation mutagenesis, X-ray crystallography of HAP:IL-17A complex, primary human cell cytokine inhibition assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of inhibitor bound at IL-17RA binding site with functional validation","pmids":["27184415"],"is_preprint":false},{"year":2022,"finding":"IL-17RA signaling in intestinal epithelium regulates secretory IgA responses against Citrobacter rodentium infection by controlling luminal hydrogen peroxide production and Tnfsf13 expression; reduced Tnfsf13 results in profound defects in generating pathogen-specific IgA+ antibody-secreting cells.","method":"Intestinal IL-17RA and IL-17RC conditional KO mice, C. rodentium infection model, luminal H2O2 measurement, Tnfsf13 expression analysis, IgA+ ASC quantification","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with mechanistic pathway linking IL-17R to IgA through Tnfsf13, single lab","pmids":["33431657"],"is_preprint":false}],"current_model":"IL-17RA functions as the central, shared receptor subunit of multiple heteromeric complexes (IL-17RA/RC for IL-17A, IL-17F, IL-17A/F, IL-17C; IL-17RA/RB for IL-17E/IL-25 and IL-17B) that form cytokine-induced hexameric signalosomes; upon ligand binding, IL-17RA dimerizes and recruits the adaptor Act1 via SEFIR-domain CC' loop interactions, leading to TRAF6 ubiquitination, NF-κB and MAPK (ERK, p38, JNK) activation, and downstream chemokine/cytokine production in structural cells (epithelial cells, fibroblasts, smooth muscle cells); cell-type-specific IL-17RA signaling governs neutrophil recruitment, mucosal barrier integrity, secretory cell differentiation in the gut, airway smooth muscle contraction (via Rab35/PKCα/stress fiber axis), osteoclast precursor abundance, and macrophage efferocytosis, while loss-of-function IL-17RA mutations in humans abolish responses to IL-17A/F and IL-17E, resulting in chronic mucocutaneous candidiasis and staphylococcal disease."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing that IL-17RA is expressed on non-immune structural cells and directly drives chemokine transcription resolved how IL-17 signals provoke neutrophilic inflammation at tissue sites.","evidence":"IL-17RA expression confirmed on human airway smooth muscle cells by RT-PCR and immunostaining; CXCL-8 promoter reporter assays with NF-κB/AP-1 site mutations","pmids":["15893694"],"confidence":"High","gaps":["Downstream adaptor proteins not yet identified","Whether other IL-17R subunits are required was unknown"]},{"year":2008,"claim":"Identifying IL-17RA as a shared subunit required for both IL-17A/F (with IL-17RC) and IL-25 (with IL-17RB) signaling established IL-17RA as the central hub of the IL-17 receptor family.","evidence":"Reciprocal KO mice (IL-17RA, IL-17RB), siRNA knockdown of IL-17RA/RC in synoviocytes and bronchial epithelial cells, SPR binding affinity measurements","pmids":["18768888","18684971","18097068"],"confidence":"High","gaps":["Structural basis for how one receptor subunit participates in distinct heteromeric complexes was unknown","Intracellular signaling domain architecture not yet mapped"]},{"year":2009,"claim":"Demonstrating that IL-17RA drives neutrophil recruitment and oxidative damage but is dispensable for viral clearance delineated the immunopathological versus protective roles of IL-17RA in infection.","evidence":"IL-17RA−/− mice in influenza infection model with dissection of neutrophil, MPO, oxidized phospholipid, and CD8+ T cell responses","pmids":["19783685"],"confidence":"High","gaps":["Cell-type-specific contributions of IL-17RA (hematopoietic vs structural) not yet resolved in this model"]},{"year":2010,"claim":"Mapping the IL-17RA intracellular signaling requirements revealed that Act1 recruitment via the SEFIR domain is necessary but insufficient, and that TRAF6 ubiquitination is the critical downstream checkpoint for NF-κB/MAPK activation.","evidence":"Structure-function mutagenesis of IL-17RA C-terminal domain; siRNA of IL-17RA/RC with NF-κB, AP-1, ERK, p38, JNK readouts in synoviocytes","pmids":["20729198","21109515"],"confidence":"High","gaps":["Precise structural interface between Act1 SEFIR and IL-17RA SEFIR not yet resolved","Additional adaptor proteins potentially involved were unknown"]},{"year":2011,"claim":"Pinpointing the CC' loop of the Act1 SEFIR domain as the critical interaction surface with IL-17RA provided a targetable interface for therapeutic disruption of IL-17 signaling.","evidence":"SPR showing direct CC' loop peptide binding to IL-17RA; cell-permeable decoy peptide inhibited IL-17 and IL-25 signaling in vitro and pulmonary inflammation in vivo","pmids":["22045852"],"confidence":"High","gaps":["Atomic-resolution structure of the Act1-IL-17RA SEFIR complex not determined","Whether the CC' loop peptide affects all IL-17RA heteromeric complexes equally was not tested"]},{"year":2011,"claim":"Identifying the pre-ligand assembly domain (PLAD) of IL-17RA as mediating receptor-chain associations before ligand binding revealed a pre-assembly mechanism for IL-17 signaling competence.","evidence":"Lentiviral delivery of IL-17RA PLAD-Ig fusion in spontaneously hypertensive rats reduced collagen/MMP production and improved cardiac function","pmids":["21530504"],"confidence":"Medium","gaps":["PLAD-mediated assembly not confirmed by structural methods","Single disease model; generalizability to other IL-17RA-dependent contexts untested","No independent replication"]},{"year":2012,"claim":"Demonstrating that IL-17RA signaling in fibroblasts and vascular cells drives inflammatory mediator production in arthritis and atherosclerosis models extended the receptor's role from antimicrobial defense to chronic inflammatory disease pathogenesis.","evidence":"IL-17RA−/− mice in K/BxN serum-transfer arthritis and ApoE−/− atherosclerosis models with defined chemokine, MMP, and leukocyte recruitment readouts","pmids":["22028860","22302786"],"confidence":"High","gaps":["Cell-type-specific conditional deletions not yet performed in these models","Relative contribution of IL-17A vs IL-17F to each disease model not dissected"]},{"year":2013,"claim":"Revealing that IL-17RA on TFH cells governs germinal center positioning via RGS16 upregulation extended IL-17RA function beyond structural cells to adaptive immune cell guidance.","evidence":"BXD2-Il17ra−/− mice, confocal microscopy of GC light zone localization, BXD2-Rgs16−/− mice phenocopy","pmids":["23858031"],"confidence":"High","gaps":["Whether this TFH-intrinsic IL-17RA role operates outside the BXD2 autoimmune context is unknown","Direct signaling cascade from IL-17RA to RGS16 transcription not mapped"]},{"year":2016,"claim":"Bone marrow chimera and conditional deletion experiments established that non-hematopoietic (structural) cells are the primary responders through IL-17RA for neutrophil-recruiting chemokine production during pulmonary infection, and that IL-17RA in osteoclast precursors promotes osteoclastogenesis.","evidence":"IL-17RA−/− bone marrow chimeras in mycobacterial infection; LysM-Cre conditional IL-17RA KO with microCT and histomorphometry","pmids":["26871571","34973492"],"confidence":"High","gaps":["Identity of specific structural cell subtype (epithelial vs fibroblast vs endothelial) driving chemokine production in infection not resolved","Osteoclast precursor study from single lab"]},{"year":2016,"claim":"Characterization of 21 patients with autosomal recessive IL-17RA deficiency definitively established IL-17RA as essential for human mucocutaneous immunity against Candida and Staphylococcus, abolishing responses to IL-17A/F and IL-17E.","evidence":"Primary fibroblast and leukocyte functional assays from patients with 12 different loss-of-function IL-17RA alleles","pmids":["27930337"],"confidence":"High","gaps":["Genotype-phenotype correlations for partial vs complete loss-of-function alleles not fully delineated","Whether residual signaling through other IL-17R complexes compensates in mild alleles was not tested"]},{"year":2018,"claim":"Identification of RKIP as a scaffolding partner that bridges IL-17RA and Act1 revealed an additional layer of regulation in IL-17R signalosome assembly, with functional consequences for Th17-driven autoimmunity.","evidence":"Co-IP of RKIP with IL-17RA and Act1; RKIP−/− mice selectively resistant to Th17- but not Th1-driven EAE","pmids":["29674348"],"confidence":"High","gaps":["Structural basis for RKIP bridging IL-17RA and Act1 unknown","Whether RKIP modulates all IL-17RA heteromeric complexes or only IL-17RA/RC not tested"]},{"year":2019,"claim":"Mapping the IL-17RA/Act1–Rab35/DennD1C–PKCα–fascin axis in airway smooth muscle established a non-canonical IL-17RA effector pathway directly linking cytokine signaling to cytoskeletal remodeling and contractile function.","evidence":"Cell-type-specific IL-17R/Act1 deletion in airway smooth muscle; Co-IP of Rab35/DennD1C with IL-17R/Act1 complex; Rab35 KD, PKCα inhibitor, stress fiber imaging","pmids":["30683702"],"confidence":"High","gaps":["Whether this cytoskeletal pathway operates in non-smooth-muscle cell types is unknown","Direct kinase-substrate relationship between PKCα and fascin at Ser39 not demonstrated in this IL-17 context by in vitro kinase assay"]},{"year":2019,"claim":"Conditional deletion of IL-17RA in intestinal epithelium revealed its role in maintaining microbiome homeostasis and preventing bacterial product translocation, and separately showed fibroblast-specific IL-17RA/STAT3 is required for vaccine-elicited pulmonary immunity.","evidence":"Intestinal epithelium-specific and fibroblast-specific IL-17RA conditional KO mice in hepatitis, C. rodentium infection, and Klebsiella vaccine models","pmids":["31747600","34516780","33431657"],"confidence":"High","gaps":["How IL-17RA regulates hydrogen peroxide production mechanistically is not resolved","Whether fibroblast IL-17RA/STAT3 axis operates in non-pulmonary mucosal tissues unknown"]},{"year":2020,"claim":"Crystal structures of IL-17RC–IL-17F and IL-17RA–IL-17RC–IL-17A complexes revealed the hexameric signalosome architecture and showed that IL-17RA dimerization is functionally required for downstream gene expression.","evidence":"X-ray crystallography of extracellular domains; IL-17RA dimerization-defective mutant with keratinocyte gene expression assays","pmids":["32187518","36260993"],"confidence":"High","gaps":["Full-length receptor complex structure including intracellular domains not determined","How hexameric assembly propagates signal across the membrane to recruit Act1 is structurally unresolved"]},{"year":2022,"claim":"Demonstrating that IL-17RA in Lgr5+ intestinal stem cells induces ATOH1 to commit secretory cell lineages revealed a regenerative, non-inflammatory function of IL-17RA in tissue homeostasis.","evidence":"Multiple conditional deletions (Lgr5-Cre, ATOH1-Cre), intestinal injury models, human organoid IL-17A stimulation","pmids":["35081371"],"confidence":"High","gaps":["Signaling intermediates between IL-17RA and ATOH1 transcriptional induction not identified","Whether this pathway is active under homeostatic conditions without injury is unclear"]},{"year":2024,"claim":"Identification of IL-17RA-dependent ADAM17-mediated MERTK shedding as the mechanism by which IL-17A impairs macrophage efferocytosis provided a mechanistic link between IL-17 signaling and failed inflammation resolution in arthritis.","evidence":"IL-17RA silencing and cyanidin treatment restored efferocytosis; ADAM17 KD phenocopied; adjuvant-induced arthritis model","pmids":["38810305"],"confidence":"Medium","gaps":["Single lab; independent replication needed","Whether MERTK shedding by IL-17RA/ADAM17 operates in tissue macrophages beyond the synovium is untested"]},{"year":2025,"claim":"Dual cell-type-specific roles of IL-17RA were delineated in colorectal cancer: suppression of EMT via EGFR/Src restraint in epithelial cells, and enabling Syk-dependent IL-18 release from macrophages for anti-tumor CD8+ T cell immunity.","evidence":"Conditional IL-17RA deletion in IECs and macrophages; CRC mouse model; EGFR/Src and dectin-1/Syk pathway analysis","pmids":["40023157"],"confidence":"High","gaps":["How IL-17RA restrains EGFR/Src mechanistically is not fully resolved","Relevance to human CRC not yet demonstrated"]},{"year":null,"claim":"A full-length structural model of the IL-17RA signalosome spanning extracellular hexamer through transmembrane to intracellular SEFIR–Act1–TRAF6 assembly remains undetermined, and cell-type-specific transcriptional programs downstream of the common IL-17RA signal are incompletely mapped.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length receptor complex structure exists","Mechanisms selecting between NF-κB, MAPK, STAT3, and non-canonical (Rab35) pathways in different cell types are unknown","How IL-17RA expression is regulated at the post-transcriptional level (beyond FTO/m6A) is poorly understood"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,9,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,9,14,34]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,11,14,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,9,22,35,37]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[15]}],"complexes":["IL-17RA/IL-17RC","IL-17RA/IL-17RB","IL-17RA/Act1/TRAF6"],"partners":["IL17RC","IL17RB","TRAF1IP2","TRAF6","PEBP1","RAB35","DENND1C"],"other_free_text":[]},"mechanistic_narrative":"IL-17RA is the obligate shared receptor subunit for multiple IL-17 family cytokines, forming heteromeric signaling complexes with IL-17RC (for IL-17A, IL-17F, and IL-17A/F) and IL-17RB (for IL-17E/IL-25 and IL-17B) that assemble into hexameric signalosomes upon ligand-induced IL-17RA dimerization [PMID:36260993, PMID:18768888, PMID:18684971, PMID:30770417]. Upon cytokine engagement, IL-17RA recruits the adaptor Act1 via SEFIR-domain CC' loop interactions, leading to TRAF6 ubiquitination and activation of NF-κB and MAPK (ERK, p38, JNK) cascades that drive chemokine and cytokine production in structural cells including epithelial cells, fibroblasts, and airway smooth muscle [PMID:22045852, PMID:20729198, PMID:21109515, PMID:15893694]. Cell-type-specific IL-17RA signaling governs neutrophil recruitment, intestinal secretory cell differentiation via ATOH1 induction in stem cells, mucosal barrier integrity through IgA and hydrogen peroxide regulation, airway smooth muscle contraction via a Rab35/PKCα/stress fiber axis, osteoclast precursor abundance, and macrophage efferocytosis through ADAM17-mediated MERTK shedding [PMID:35081371, PMID:30683702, PMID:33431657, PMID:34973492, PMID:38810305, PMID:26871571]. Autosomal recessive loss-of-function mutations in IL-17RA abolish responses to IL-17A/F and IL-17E, causing chronic mucocutaneous candidiasis and staphylococcal disease [PMID:27930337]."},"prefetch_data":{"uniprot":{"accession":"Q96F46","full_name":"Interleukin-17 receptor A","aliases":["CDw217"],"length_aa":866,"mass_kda":96.1,"function":"Receptor for IL17A and IL17F, major effector cytokines of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity. Receptor for IL17A (PubMed:17911633, PubMed:9367539). Receptor for IL17F (PubMed:17911633, PubMed:19838198). Binds to IL17A with higher affinity than to IL17F (PubMed:17911633). Binds IL17A and IL17F homodimers as part of a heterodimeric complex with IL17RC (PubMed:16785495). Also binds heterodimers formed by IL17A and IL17F as part of a heterodimeric complex with IL17RC (PubMed:18684971). Cytokine binding triggers homotypic interaction of IL17RA and IL17RC chains with TRAF3IP2 adapter, leading to TRAF6-mediated activation of NF-kappa-B and MAPkinase pathways, ultimately resulting in transcriptional activation of cytokines, chemokines, antimicrobial peptides and matrix metalloproteinases, with potential strong immune inflammation (PubMed:16785495, PubMed:17911633, PubMed:18684971, PubMed:21350122, PubMed:24120361). Involved in antimicrobial host defense primarily promoting neutrophil activation and recruitment at infection sites to destroy extracellular bacteria and fungi (By similarity). In secondary lymphoid organs, contributes to germinal center formation by regulating the chemotactic response of B cells to CXCL12 and CXCL13, enhancing retention of B cells within the germinal centers, B cell somatic hypermutation rate and selection toward plasma cells (By similarity). Plays a role in the maintenance of the integrity of epithelial barriers during homeostasis and pathogen infection. Stimulates the production of antimicrobial beta-defensins DEFB1, DEFB103A, and DEFB104A by mucosal epithelial cells, limiting the entry of microbes through the epithelial barriers (By similarity). Involved in antiviral host defense through various mechanisms. Enhances immunity against West Nile virus by promoting T cell cytotoxicity. Contributes to Influenza virus clearance by driving the differentiation of B-1a B cells, providing for production of virus-specific IgM antibodies at first line of host defense (By similarity). Receptor for IL17C as part of a heterodimeric complex with IL17RE (PubMed:21993848) (Microbial infection) Receptor for SARS coronavirus-2/SARS-CoV-2 virus protein ORF8, leading to IL17 pathway activation and an increased secretion of pro-inflammatory factors through activating NF-kappa-B signaling pathway","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q96F46/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL17RA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IL17RA","total_profiled":1310},"omim":[{"mim_id":"614995","title":"INTERLEUKIN 17 RECEPTOR E; IL17RE","url":"https://www.omim.org/entry/614995"},{"mim_id":"613956","title":"CANDIDIASIS, FAMILIAL, 6; CANDF6","url":"https://www.omim.org/entry/613956"},{"mim_id":"613953","title":"IMMUNODEFICIENCY 51; IMD51","url":"https://www.omim.org/entry/613953"},{"mim_id":"610925","title":"INTERLEUKIN 17 RECEPTOR C; IL17RC","url":"https://www.omim.org/entry/610925"},{"mim_id":"607043","title":"TRAF3-INTERACTING PROTEIN 2; TRAF3IP2","url":"https://www.omim.org/entry/607043"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":33.1}],"url":"https://www.proteinatlas.org/search/IL17RA"},"hgnc":{"alias_symbol":["hIL-17R","IL-17RA","CDw217","CD217"],"prev_symbol":["IL17R"]},"alphafold":{"accession":"Q96F46","domains":[{"cath_id":"2.60.40.2160","chopping":"34-194","consensus_level":"high","plddt":90.0517,"start":34,"end":194},{"cath_id":"2.60.40.2150","chopping":"204-302","consensus_level":"high","plddt":90.699,"start":204,"end":302},{"cath_id":"3.40.50.11530","chopping":"379-589","consensus_level":"high","plddt":86.7589,"start":379,"end":589}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96F46","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96F46-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96F46-F1-predicted_aligned_error_v6.png","plddt_mean":68.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL17RA","jax_strain_url":"https://www.jax.org/strain/search?query=IL17RA"},"sequence":{"accession":"Q96F46","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96F46.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96F46/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96F46"}},"corpus_meta":[{"pmid":"24918373","id":"PMC_24918373","title":"Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis.","date":"2014","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24918373","citation_count":307,"is_preprint":false},{"pmid":"19783685","id":"PMC_19783685","title":"Critical role of IL-17RA in immunopathology of influenza infection.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19783685","citation_count":296,"is_preprint":false},{"pmid":"18768888","id":"PMC_18768888","title":"Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18768888","citation_count":277,"is_preprint":false},{"pmid":"18684971","id":"PMC_18684971","title":"The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18684971","citation_count":246,"is_preprint":false},{"pmid":"33789737","id":"PMC_33789737","title":"Exosomes derived from human adipose mesenchymal stem cells attenuate hypertrophic scar fibrosis by miR-192-5p/IL-17RA/Smad axis.","date":"2021","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33789737","citation_count":212,"is_preprint":false},{"pmid":"21647421","id":"PMC_21647421","title":"IL-17RA is required for CCL2 expression, macrophage recruitment, and emphysema in response to cigarette smoke.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21647421","citation_count":186,"is_preprint":false},{"pmid":"30604628","id":"PMC_30604628","title":"Profibrotic effect of IL-17A and elevated IL-17RA in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated lung disease support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease.","date":"2019","source":"American journal of physiology. 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knockout of either subunit or antibody blockade of either receptor abolishes IL-25-induced IL-5/IL-13 production and pulmonary inflammation in vivo.\",\n      \"method\": \"Knockout mice (IL-17RB KO and IL-17RA KO), antagonistic monoclonal antibodies, in vitro splenocyte assays, intranasal IL-25 challenge model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal KO + antibody blockade, replicated across in vitro and in vivo systems in same study\",\n      \"pmids\": [\"18768888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex; IL-17RA binds IL-17A with higher affinity than IL-17F or the heterodimer (measured by surface plasmon resonance), while IL-17RC binds all three cytokines with comparable affinity; soluble IL-17RA preferentially neutralizes IL-17A activity.\",\n      \"method\": \"siRNA knockdown of IL-17RA and IL-17RC, surface plasmon resonance (binding affinity), soluble receptor neutralization assays, bronchial epithelial cell cytokine secretion assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biophysical binding measurements + functional siRNA knockdown + soluble receptor assays, multiple orthogonal methods\",\n      \"pmids\": [\"18684971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Both IL-17RA and IL-17RC are required for IL-17A-induced ELR+ CXC chemokine (IL-6, IL-8, CCL-20) expression in synoviocytes; siRNA silencing of either receptor abrogates IL-17A-mediated signaling, and combined inhibition is required when TNF-α is also present.\",\n      \"method\": \"siRNA knockdown of IL-17RA and IL-17RC in rheumatoid arthritis synoviocytes, ELISA, microarray gene expression analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with defined cytokine readouts, multiple orthogonal methods\",\n      \"pmids\": [\"18097068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-17RA-mediated signaling requires an extended C-terminal domain beyond the previously identified SEFIR motif; Act1 recruitment to IL-17RA is necessary but not sufficient for downstream signaling, whereas TRAF6 ubiquitination correlates tightly with functional receptor activity. IL-17RA signals synergistically with lymphotoxin-α3 using the same signaling motifs.\",\n      \"method\": \"Structure-function mutagenesis of IL-17RA C-terminal domain, Act1 recruitment assays, TRAF6 ubiquitination assays, cell-based signaling readouts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — detailed mutagenesis with multiple functional readouts in same study\",\n      \"pmids\": [\"20729198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The CC' loop of the SEFIR domain of Act1 directly mediates interaction with IL-17RA; a cell-permeable decoy peptide based on the CC' loop sequence inhibits IL-17- and IL-25-mediated signaling in vitro and pulmonary inflammation in vivo. Deletion of the BB' loop (unlike in TIR domains) does not affect Act1-IL-17RA interaction.\",\n      \"method\": \"Domain deletion mutagenesis, surface plasmon resonance (direct binding of CC' loop peptide to IL-17RA), cell-permeable peptide in vitro and in vivo inhibition, pulmonary inflammation mouse model\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biophysical binding + mutagenesis + in vivo functional validation, multiple orthogonal approaches\",\n      \"pmids\": [\"22045852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-17RA signaling is required for CCL2 and MMP12 expression and macrophage recruitment in the lung in response to cigarette smoke; IL-17RA-deficient mice fail to develop emphysema after 6 months of cigarette smoke exposure.\",\n      \"method\": \"IL-17RA knockout mice, cigarette smoke exposure model, qPCR for CCL2/MMP12, histological assessment of emphysema\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular and molecular phenotypes, in vivo model\",\n      \"pmids\": [\"21647421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-17RA signaling amplifies inflammatory arthritis by directly activating synovial fibroblasts to produce multiple pro-inflammatory mediators (CXCL1, CXCL2, CXCL5, IL-1β, IL-6, RANKL, MMP2, MMP3, MMP13); IL-17RA-deficient mice show reduced cartilage and bone erosions in the K/BxN serum-transfer arthritis model.\",\n      \"method\": \"IL-17RA knockout mice in K/BxN serum-transfer arthritis model, qPCR for cytokines/chemokines, in vitro IL-17A stimulation of synovial fibroblasts, histological bone/cartilage assessment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with defined molecular phenotypes confirmed by in vitro fibroblast studies\",\n      \"pmids\": [\"22028860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-17RA signaling in the aortic vasculature promotes atherosclerotic plaque formation by inducing aortic chemokines (TNFα, CXCL2) and supporting monocyte/neutrophil adherence and recruitment to the aortic arch; IL-17RA-deficient Apoe-/- mice show reduced aortic arch atherosclerosis.\",\n      \"method\": \"IL-17RA-/- x Apoe-/- double-knockout mice, Western diet feeding, flow cytometry, ex vivo monocyte adhesion assays, short-term adoptive transfer homing experiments\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with multiple orthogonal assays including ex vivo adhesion and adoptive transfer\",\n      \"pmids\": [\"22302786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-17RA expressed on follicular T helper (TFH) cells is required for their localization to the germinal center light zone and interaction with B cells; IL-17 upregulates RGS16 in TFH cells to promote TFH-B cell conjugate formation, leading to autoantibody-producing B cell generation in BXD2 mice.\",\n      \"method\": \"BXD2-Il17ra-/- mice, conditional IL-17R:Fc blockade, confocal microscopy of GC light zone localization, in vitro B cell response assays, RGS16 expression analysis, BXD2-Rgs16-/- mice\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO + blocking experiments + defined molecular mechanism (RGS16), confirmed by additional KO line\",\n      \"pmids\": [\"23858031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Inherited autosomal recessive IL-17RA deficiency in humans abolishes cellular responses to IL-17A, IL-17F homodimers, IL-17A/F heterodimers (in fibroblasts), and IL-17E/IL-25 (in leukocytes), establishing IL-17RA as essential for mucocutaneous immunity to Candida and Staphylococcus.\",\n      \"method\": \"Primary fibroblast and leukocyte functional assays from 21 patients with defined IL-17RA loss-of-function mutations; surface expression of 12 different IL-17RA alleles characterized\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct functional cellular assays in primary patient cells with multiple defined loss-of-function alleles, replicated across 21 patients\",\n      \"pmids\": [\"27930337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cyanidin specifically binds to an IL-17A-binding site on IL-17RA, blocking the IL-17A/IL-17RA protein-protein interaction; this inhibits IL-17A-induced skin hyperplasia and TH17-mediated airway inflammation in vivo.\",\n      \"method\": \"Structure-based virtual screening, molecular binding assays, murine skin hyperplasia model, murine asthma models, selectivity testing against TH1/TH2-mediated inflammation\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structure-based identification + multiple in vivo mechanistic validation models\",\n      \"pmids\": [\"28223414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RKIP (Raf-1 kinase inhibitor protein) directly interacts with both IL-17RA and Act1 to promote formation of the IL-17R-Act1 signaling complex, resulting in enhanced MAPK and NF-κB activation and downstream inflammatory cytokine production; RKIP deficiency ameliorates experimental autoimmune encephalomyelitis (EAE) by impeding Th17- but not Th1-mediated responses.\",\n      \"method\": \"Co-immunoprecipitation of RKIP with IL-17RA and Act1, adoptive T-cell transfer (Th17 vs Th1), RKIP-deficient mice in EAE model, cytokine/chemokine production assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct Co-IP showing complex formation + KO with defined mechanistic pathway + adoptive transfer selectivity\",\n      \"pmids\": [\"29674348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17A recruits Rab35 (and its GEF DennD1C) to the IL-17R/Act1 complex in airway smooth muscle cells, activating Rab35 to promote PKCα activation and fascin phosphorylation at Ser39, allowing F-actin/myosin stress fiber formation and enhanced airway smooth muscle contraction.\",\n      \"method\": \"Cell type-specific IL-17R/Act1 deletion, Co-IP of Rab35/DennD1C with IL-17R/Act1 complex, Rab35 knockdown, PKCα inhibitor, immunofluorescence for stress fibers, airway smooth muscle contraction assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP of complex + conditional deletion + multiple mechanistic steps validated with inhibitors and knockdown\",\n      \"pmids\": [\"30683702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the extracellular domain of IL-17RC in complex with IL-17F reveals that IL-17RC forms a symmetrical 2:1 complex with IL-17F, competing with IL-17RA for cytokine binding; IL-17A and IL-17A/F heterodimer also form 2:1 complexes with IL-17RC, demonstrating the structural basis for potential IL-17RA-independent signaling.\",\n      \"method\": \"X-ray crystallography of IL-17RC:IL-17F complex, biophysical techniques to characterize IL-17A and IL-17A/F complexes with IL-17RC\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure determination with biophysical validation\",\n      \"pmids\": [\"32187518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-17A, IL-17F, and IL-17A/F induce IL-17RA dimerization; X-ray crystallography of the heteromeric IL-17A complex with extracellular domains of IL-17RA and IL-17RC reveals a 2:2:2 hexameric signaling assembly (signalosome); formation of this signalosome potentiates IL-17-induced IL-36γ and CXCL1 expression in human keratinocytes compared to a dimerization-defective IL-17RA variant.\",\n      \"method\": \"X-ray crystallography, biophysical binding studies, mutagenesis of IL-17RA dimerization interface, keratinocyte gene expression assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure + mutagenesis + functional validation in primary cells\",\n      \"pmids\": [\"36260993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-17RA signaling in Lgr5+ intestinal stem cells induces ATOH1 transcription factor expression to promote secretory cell lineage commitment (Paneth, tuft, goblet, enteroendocrine cells); IL-17RA signaling in ATOH1+ cells is required to regenerate secretory cells following injury; IL-17A stimulation of human intestinal organoids rescues secretory cell differentiation.\",\n      \"method\": \"Multiple conditional deletion models (Lgr5-Cre, ATOH1-Cre), intestinal injury models, human intestinal organoid stimulation, lineage tracing, cell counting\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple conditional KO models + organoid functional validation + defined transcription factor mechanism\",\n      \"pmids\": [\"35081371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FTO (fat mass and obesity-associated RNA demethylase) reduces m6A methylation of IL-17RA mRNA in liver tissue, increasing IL-17RA expression and promoting chronic hepatic inflammation; knockdown and overexpression of FTO in vitro and in vivo confirm FTO as the main modulator of IL-17RA m6A levels.\",\n      \"method\": \"MeRIP-seq on human liver tissues, FTO knockdown/overexpression in vitro and in vivo, NAFLD and chronic liver injury mouse models, comparison with METTL3, METTL14, ALKBH5\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MeRIP-seq + KD/OE functional validation, single lab but orthogonal in vitro/in vivo approach\",\n      \"pmids\": [\"36172147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17A signals through the IL-17A/IL-17RA/p-STAT3/FABP4 axis in ovarian cancer cells to promote fatty acid uptake and cancer cell proliferation in an adipocyte-rich microenvironment; this is dependent on IL-17RA but not CD36.\",\n      \"method\": \"In vitro palmitic acid uptake assays with IL-17A stimulation, IL-17RA pathway analysis, orthotopic implantation model in IL-17A-deficient mice, FABP4 and p-STAT3 expression analysis\",\n      \"journal\": \"Cancer immunology, immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanistic pathway + in vivo KO model, single lab\",\n      \"pmids\": [\"31802182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-17A and IL-17F both signal through IL-17RA and IL-17RC in rheumatoid synoviocytes activating NF-κB and MAPKs; siRNA silencing of either receptor nearly completely abrogates IL-17A-mediated IL-6 expression and IL-17F+TNF-α-mediated responses; IL-17A activates ERK, p38, JNK and induces TRAF6 but not MyD88.\",\n      \"method\": \"Affymetrix microarrays, ELISA, siRNA knockdown of IL-17RA/RC, Western blotting, NF-κB and AP-1 DNA binding assays\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA + multiple signaling readouts, orthogonal approaches\",\n      \"pmids\": [\"21109515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A soluble isoform of human IL-17RA is generated by alternative splicing (exclusion of exon 11 encoding the transmembrane region) and is secreted into cell culture media, providing a potential endogenous regulator of IL-17RA-mediated responses.\",\n      \"method\": \"RT-PCR in human tissues, Western blotting of culture media to detect soluble isoform protein\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular characterization at mRNA and protein level, but functional consequences not directly measured\",\n      \"pmids\": [\"24084331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17RA signaling in intestinal epithelial cells regulates the microbiome and constrains bacterial product (CpG DNA) translocation to the liver; absence of intestinal epithelial IL-17RA leads to microbiome dysbiosis, increased hepatic IL-18 production, and exacerbated immune-driven hepatitis.\",\n      \"method\": \"Intestinal epithelium-specific IL-17RA-deficient mice (conditional KO), immune-driven hepatitis model, microbiome analysis, bacterial product translocation assays, IL-18 measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific conditional KO with defined mechanistic pathway linking intestinal IL-17RA to liver disease via microbiome\",\n      \"pmids\": [\"31747600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17RA signaling in non-hematopoietic lung fibroblasts (rather than hematopoietic cells) is required for vaccine-elicited TH17-mediated lung-specific immunity to Klebsiella pneumoniae, acting through STAT3 expression.\",\n      \"method\": \"Fibroblast-specific IL-17RA deletion, STAT3-deficient mice, adoptive transfer of vaccine-elicited CD4+ T cells, lung-specific immunity readouts\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type specific conditional deletion identifying fibroblast IL-17RA as the functional signal transducer\",\n      \"pmids\": [\"34516780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17RA expressed on non-hematopoietic (structural) lung cells is required for CXCL-1 and CXCL-5 production and subsequent adaptive neutrophil recruitment during Mycobacteria infection; CXCL-1/5 instillation rescues neutrophil recruitment in IL-17RA-/- mice.\",\n      \"method\": \"IL-17RA-/- mice, BCG/Mtb intranasal infection model, bone marrow chimeras to distinguish hematopoietic vs non-hematopoietic IL-17RA, CXCL-1/5 reconstitution experiment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO + bone marrow chimeras + cytokine reconstitution, multiple complementary approaches\",\n      \"pmids\": [\"26871571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17A signals through IL-17RA to activate NF-κB-mediated fibrogenic responses in lung fibroblasts (ECM production, myofibroblast transdifferentiation, proliferation); siRNA silencing of IL-17RA attenuates these responses; JAK2 (but not JAK1/3) is also required for IL-17A-induced fibrogenic responses in fibroblasts.\",\n      \"method\": \"siRNA silencing of IL-17RA in normal and IPF fibroblasts, NF-κB inhibition, JAK2 siRNA and selective pharmacological inhibitors (AZD1480 vs tofacitinib), ECM protein measurement, myofibroblast marker assays\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA + selective pharmacological inhibitors with multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"30604628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17B signals through IL-17RA and IL-17RB receptor subunits (like IL-25/IL-17E) to induce type 2 cytokine secretion from human innate type 2 lymphocytes, NKT, and Th2 cells; IL-17B can augment IL-33-driven type 2 responses.\",\n      \"method\": \"Receptor subunit blocking antibodies and genetic dependence studies in human primary lymphocytes, cytokine secretion assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody-based receptor blockade in primary human cells, single lab\",\n      \"pmids\": [\"30770417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-17RA in intestinal epithelial cells (IECs) suppresses EMT via restraint of EGFR/Src signaling; in macrophages, IL-17RA is required for Syk kinase activation upon dectin-1 engagement by fungi, enabling IL-18 release and protective CD8+ T cell anti-tumor immunity in colorectal cancer.\",\n      \"method\": \"Conditional IL-17RA deletion in IECs and macrophages, CRC mouse model, EGFR/Src pathway analysis, dectin-1/Syk signaling assays, IL-18 measurement, CD8+ T cell functional readouts, combinatorial immunotherapy experiments\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific conditional KOs revealing two distinct IL-17RA signaling mechanisms in distinct cell types, multiple orthogonal readouts\",\n      \"pmids\": [\"40023157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17RA in osteoclast precursors (conditional deletion with LysM-Cre) promotes osteoclast formation and subsequent bone resorption; IL-17ra conditional KO mice display increased trabecular bone mass due to reduced osteoclast precursor abundance.\",\n      \"method\": \"LysM-Cre conditional IL-17ra knockout, microCT bone analysis, histomorphometry, in vitro osteoclast differentiation assays\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell type-specific conditional KO with defined in vivo and in vitro phenotypes, single lab\",\n      \"pmids\": [\"34973492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Gingerenone A (GA) directly binds IL-17RA protein to inhibit IL-17 signaling; lentivirus-mediated IL-17RA/Act1 knockdown or co-treatment with brodalumab/ixekizumab impairs GA's protective effects against DSS-induced colitis, confirming IL-17RA as the molecular target.\",\n      \"method\": \"Pull-down assay, surface plasmon resonance, molecular dynamics simulation, lentiviral IL-17RA/Act1 knockdown, DSS-induced colitis mouse model, brodalumab/ixekizumab co-treatment\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding confirmed by SPR + MD simulation + genetic/pharmacological loss-of-function\",\n      \"pmids\": [\"38639442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17A signaling through IL-17RA promotes MMP-2 and MMP-9 expression and NSCLC cell invasion via p38 MAPK pathway; p38 MAPK-specific inhibitor SB203580 suppresses IL-17RA-dependent migration and invasion; MMP-2/9 are downstream effectors of the IL-17RA/p38 axis.\",\n      \"method\": \"IL-17RA overexpression/knockdown in NSCLC cell lines, p38 MAPK inhibitor (SB203580), wound healing/Transwell invasion assays, Western blotting\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD/OE with pharmacological inhibitor confirming pathway, single lab\",\n      \"pmids\": [\"30564960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17 regulates Cyr61, IL-23, GM-CSF, and RANKL expression in fibroblast-like synoviocytes via an IL-17RA/STAT-3 signaling cascade; IL-17RA knockdown reverses IL-17-induced SHP-2 upregulation and abolishes the osteoclastogenic potential of IL-17-treated FLS.\",\n      \"method\": \"siRNA knockdown of IL-17RA, STAT-3 inhibitor (S3I-201), co-culture osteoclast differentiation assays, Western blotting, TRAP staining\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — siRNA + pharmacological inhibitor with multiple readouts, single lab\",\n      \"pmids\": [\"28898718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17RA/Act1 signaling is required for IL-17RA dimerization following IL-17A stimulation of airway smooth muscle cells; IL-17RA signaling also requires cell-type-specific Act1 for its direct effect on airway smooth muscle contraction.\",\n      \"method\": \"Cell type-specific deletion of IL-17R and Act1 in airway smooth muscle cells, Co-IP for complex formation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell type-specific deletion with functional airway contraction readout\",\n      \"pmids\": [\"30683702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Oxidative stress induces KLF4 transcription factor, which directly activates IL-17RA expression in retinal pigment epithelial cells, leading to IL-1β and IL-8 production; IL-17RA knockdown prevents OS-induced RPE apoptosis and inflammatory response.\",\n      \"method\": \"siRNA knockdown of IL-17RA and KLF4, promoter-binding assays, flow cytometry for apoptosis, AMD-like mouse model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — transcriptional regulation mechanism with KD functional validation, single lab\",\n      \"pmids\": [\"31881336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-17A impedes efferocytosis in synovial macrophages via preferential activation of JAK/STAT-3/ADAM17 signaling axis, causing ADAM17-mediated shedding of MERTK; disruption of IL-17A/IL-17RA interaction (by cyanidin or IL-17RA silencing) abolishes ADAM17 expression, reduces MERTK shedding, and restores efferocytosis.\",\n      \"method\": \"IL-17RA silencing, cyanidin treatment, ADAM17 knockdown, MERTK shedding assays, efferocytosis functional assays, flow cytometry for macrophage phenotype, adjuvant-induced arthritis model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic + pharmacological IL-17RA blockade with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"38810305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17RA-/- mesenchymal stem cells (MSCs) lose immunosuppressive function in experimental autoimmune encephalomyelitis; IL-17RA-/- MSCs fail to reduce Th17 cell frequency and fail to generate CD4+CD25+Foxp3+ Tregs, correlating with reduced VCAM1, ICAM1, and PD-L1 expression on MSCs.\",\n      \"method\": \"IL-17RA-/- MSCs in EAE model, adoptive transfer, flow cytometry, gene expression analysis of immunosuppressive mediators\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO MSCs in defined in vivo model with mechanistic readouts, single lab\",\n      \"pmids\": [\"29760692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IL-17 receptor (IL-17RA) is expressed on human airway smooth muscle cells; IL-17 induces CXCL-8 production via transcriptional mechanisms dependent on NF-κB and AP-1 binding sites in the CXCL-8 promoter; transcriptional inhibitor actinomycin D abolishes this response.\",\n      \"method\": \"IL-17R expression by RT-PCR, Western blotting, and surface immunostaining; CXCL-8 promoter reporter assays with wild-type and site-specific mutant constructs; actinomycin D inhibition\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — promoter mutagenesis + reporter assays with multiple validation methods\",\n      \"pmids\": [\"15893694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17RA signaling is required for weight loss, neutrophil migration, MPO accumulation, and oxidized phospholipid generation in the lung during influenza infection, but is dispensable for CD8+ T cell recruitment and viral clearance.\",\n      \"method\": \"IL-17RA-/- mice in influenza infection model, bronchoalveolar lavage cell counting, MPO measurement, oxidized phospholipid quantification, flow cytometric analysis of influenza-specific CD8+ T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with multiple mechanistic dissection of IL-17RA-dependent vs -independent pathways\",\n      \"pmids\": [\"19783685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The pre-ligand assembly domain (PLAD) of IL-17RA mediates receptor-chain associations essential for IL-17 signaling; blocking IL-17RA PLAD with an Ig fusion protein reduces myocardial collagen production (MMP-2, MMP-9, TIMP-1, -2, collagen I/III) and improves diastolic cardiac function in spontaneously hypertensive rats.\",\n      \"method\": \"Lentiviral delivery of IL-17RA PLAD-Ig in spontaneously hypertensive rats, echocardiography, immunoblotting for MMP/TIMP/collagen, collagen quantitation\",\n      \"journal\": \"Experimental and molecular pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo PLAD blockade with defined molecular and functional readouts, single lab\",\n      \"pmids\": [\"21530504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17RA signaling in CD8+ T cells is intrinsically required for maintenance of functional effector CD8+ T cells during Trypanosoma cruzi infection; in vitro recombinant IL-17 downregulates pro-apoptotic protein BAD and promotes CD8+ T cell survival.\",\n      \"method\": \"IL-17RA KO mice in T. cruzi infection model, adoptive transfer experiments, intracellular BAD expression analysis, PD-L1 blockade, transcriptomic profiling\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO + adoptive transfer establishing cell-intrinsic requirement + defined molecular (BAD) mechanism\",\n      \"pmids\": [\"30364284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A linear 15-residue peptide antagonist (HAP) binds IL-17A and blocks IL-17RA binding; crystal structure shows two HAP molecules bind one IL-17A dimer symmetrically, with N-terminal portions forming a β-strand inserted between IL-17A monomers and C-terminal helix directly blocking the IL-17RA binding site on IL-17A.\",\n      \"method\": \"Phage-display peptide screening, saturation mutagenesis, X-ray crystallography of HAP:IL-17A complex, primary human cell cytokine inhibition assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of inhibitor bound at IL-17RA binding site with functional validation\",\n      \"pmids\": [\"27184415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-17RA signaling in intestinal epithelium regulates secretory IgA responses against Citrobacter rodentium infection by controlling luminal hydrogen peroxide production and Tnfsf13 expression; reduced Tnfsf13 results in profound defects in generating pathogen-specific IgA+ antibody-secreting cells.\",\n      \"method\": \"Intestinal IL-17RA and IL-17RC conditional KO mice, C. rodentium infection model, luminal H2O2 measurement, Tnfsf13 expression analysis, IgA+ ASC quantification\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with mechanistic pathway linking IL-17R to IgA through Tnfsf13, single lab\",\n      \"pmids\": [\"33431657\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17RA functions as the central, shared receptor subunit of multiple heteromeric complexes (IL-17RA/RC for IL-17A, IL-17F, IL-17A/F, IL-17C; IL-17RA/RB for IL-17E/IL-25 and IL-17B) that form cytokine-induced hexameric signalosomes; upon ligand binding, IL-17RA dimerizes and recruits the adaptor Act1 via SEFIR-domain CC' loop interactions, leading to TRAF6 ubiquitination, NF-κB and MAPK (ERK, p38, JNK) activation, and downstream chemokine/cytokine production in structural cells (epithelial cells, fibroblasts, smooth muscle cells); cell-type-specific IL-17RA signaling governs neutrophil recruitment, mucosal barrier integrity, secretory cell differentiation in the gut, airway smooth muscle contraction (via Rab35/PKCα/stress fiber axis), osteoclast precursor abundance, and macrophage efferocytosis, while loss-of-function IL-17RA mutations in humans abolish responses to IL-17A/F and IL-17E, resulting in chronic mucocutaneous candidiasis and staphylococcal disease.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-17RA is the obligate shared receptor subunit for multiple IL-17 family cytokines, forming heteromeric signaling complexes with IL-17RC (for IL-17A, IL-17F, and IL-17A/F) and IL-17RB (for IL-17E/IL-25 and IL-17B) that assemble into hexameric signalosomes upon ligand-induced IL-17RA dimerization [PMID:36260993, PMID:18768888, PMID:18684971, PMID:30770417]. Upon cytokine engagement, IL-17RA recruits the adaptor Act1 via SEFIR-domain CC' loop interactions, leading to TRAF6 ubiquitination and activation of NF-κB and MAPK (ERK, p38, JNK) cascades that drive chemokine and cytokine production in structural cells including epithelial cells, fibroblasts, and airway smooth muscle [PMID:22045852, PMID:20729198, PMID:21109515, PMID:15893694]. Cell-type-specific IL-17RA signaling governs neutrophil recruitment, intestinal secretory cell differentiation via ATOH1 induction in stem cells, mucosal barrier integrity through IgA and hydrogen peroxide regulation, airway smooth muscle contraction via a Rab35/PKCα/stress fiber axis, osteoclast precursor abundance, and macrophage efferocytosis through ADAM17-mediated MERTK shedding [PMID:35081371, PMID:30683702, PMID:33431657, PMID:34973492, PMID:38810305, PMID:26871571]. Autosomal recessive loss-of-function mutations in IL-17RA abolish responses to IL-17A/F and IL-17E, causing chronic mucocutaneous candidiasis and staphylococcal disease [PMID:27930337].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that IL-17RA is expressed on non-immune structural cells and directly drives chemokine transcription resolved how IL-17 signals provoke neutrophilic inflammation at tissue sites.\",\n      \"evidence\": \"IL-17RA expression confirmed on human airway smooth muscle cells by RT-PCR and immunostaining; CXCL-8 promoter reporter assays with NF-κB/AP-1 site mutations\",\n      \"pmids\": [\"15893694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream adaptor proteins not yet identified\", \"Whether other IL-17R subunits are required was unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying IL-17RA as a shared subunit required for both IL-17A/F (with IL-17RC) and IL-25 (with IL-17RB) signaling established IL-17RA as the central hub of the IL-17 receptor family.\",\n      \"evidence\": \"Reciprocal KO mice (IL-17RA, IL-17RB), siRNA knockdown of IL-17RA/RC in synoviocytes and bronchial epithelial cells, SPR binding affinity measurements\",\n      \"pmids\": [\"18768888\", \"18684971\", \"18097068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how one receptor subunit participates in distinct heteromeric complexes was unknown\", \"Intracellular signaling domain architecture not yet mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that IL-17RA drives neutrophil recruitment and oxidative damage but is dispensable for viral clearance delineated the immunopathological versus protective roles of IL-17RA in infection.\",\n      \"evidence\": \"IL-17RA−/− mice in influenza infection model with dissection of neutrophil, MPO, oxidized phospholipid, and CD8+ T cell responses\",\n      \"pmids\": [\"19783685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contributions of IL-17RA (hematopoietic vs structural) not yet resolved in this model\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapping the IL-17RA intracellular signaling requirements revealed that Act1 recruitment via the SEFIR domain is necessary but insufficient, and that TRAF6 ubiquitination is the critical downstream checkpoint for NF-κB/MAPK activation.\",\n      \"evidence\": \"Structure-function mutagenesis of IL-17RA C-terminal domain; siRNA of IL-17RA/RC with NF-κB, AP-1, ERK, p38, JNK readouts in synoviocytes\",\n      \"pmids\": [\"20729198\", \"21109515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise structural interface between Act1 SEFIR and IL-17RA SEFIR not yet resolved\", \"Additional adaptor proteins potentially involved were unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Pinpointing the CC' loop of the Act1 SEFIR domain as the critical interaction surface with IL-17RA provided a targetable interface for therapeutic disruption of IL-17 signaling.\",\n      \"evidence\": \"SPR showing direct CC' loop peptide binding to IL-17RA; cell-permeable decoy peptide inhibited IL-17 and IL-25 signaling in vitro and pulmonary inflammation in vivo\",\n      \"pmids\": [\"22045852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of the Act1-IL-17RA SEFIR complex not determined\", \"Whether the CC' loop peptide affects all IL-17RA heteromeric complexes equally was not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying the pre-ligand assembly domain (PLAD) of IL-17RA as mediating receptor-chain associations before ligand binding revealed a pre-assembly mechanism for IL-17 signaling competence.\",\n      \"evidence\": \"Lentiviral delivery of IL-17RA PLAD-Ig fusion in spontaneously hypertensive rats reduced collagen/MMP production and improved cardiac function\",\n      \"pmids\": [\"21530504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PLAD-mediated assembly not confirmed by structural methods\", \"Single disease model; generalizability to other IL-17RA-dependent contexts untested\", \"No independent replication\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that IL-17RA signaling in fibroblasts and vascular cells drives inflammatory mediator production in arthritis and atherosclerosis models extended the receptor's role from antimicrobial defense to chronic inflammatory disease pathogenesis.\",\n      \"evidence\": \"IL-17RA−/− mice in K/BxN serum-transfer arthritis and ApoE−/− atherosclerosis models with defined chemokine, MMP, and leukocyte recruitment readouts\",\n      \"pmids\": [\"22028860\", \"22302786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific conditional deletions not yet performed in these models\", \"Relative contribution of IL-17A vs IL-17F to each disease model not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealing that IL-17RA on TFH cells governs germinal center positioning via RGS16 upregulation extended IL-17RA function beyond structural cells to adaptive immune cell guidance.\",\n      \"evidence\": \"BXD2-Il17ra−/− mice, confocal microscopy of GC light zone localization, BXD2-Rgs16−/− mice phenocopy\",\n      \"pmids\": [\"23858031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this TFH-intrinsic IL-17RA role operates outside the BXD2 autoimmune context is unknown\", \"Direct signaling cascade from IL-17RA to RGS16 transcription not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Bone marrow chimera and conditional deletion experiments established that non-hematopoietic (structural) cells are the primary responders through IL-17RA for neutrophil-recruiting chemokine production during pulmonary infection, and that IL-17RA in osteoclast precursors promotes osteoclastogenesis.\",\n      \"evidence\": \"IL-17RA−/− bone marrow chimeras in mycobacterial infection; LysM-Cre conditional IL-17RA KO with microCT and histomorphometry\",\n      \"pmids\": [\"26871571\", \"34973492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of specific structural cell subtype (epithelial vs fibroblast vs endothelial) driving chemokine production in infection not resolved\", \"Osteoclast precursor study from single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Characterization of 21 patients with autosomal recessive IL-17RA deficiency definitively established IL-17RA as essential for human mucocutaneous immunity against Candida and Staphylococcus, abolishing responses to IL-17A/F and IL-17E.\",\n      \"evidence\": \"Primary fibroblast and leukocyte functional assays from patients with 12 different loss-of-function IL-17RA alleles\",\n      \"pmids\": [\"27930337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlations for partial vs complete loss-of-function alleles not fully delineated\", \"Whether residual signaling through other IL-17R complexes compensates in mild alleles was not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of RKIP as a scaffolding partner that bridges IL-17RA and Act1 revealed an additional layer of regulation in IL-17R signalosome assembly, with functional consequences for Th17-driven autoimmunity.\",\n      \"evidence\": \"Co-IP of RKIP with IL-17RA and Act1; RKIP−/− mice selectively resistant to Th17- but not Th1-driven EAE\",\n      \"pmids\": [\"29674348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for RKIP bridging IL-17RA and Act1 unknown\", \"Whether RKIP modulates all IL-17RA heteromeric complexes or only IL-17RA/RC not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapping the IL-17RA/Act1–Rab35/DennD1C–PKCα–fascin axis in airway smooth muscle established a non-canonical IL-17RA effector pathway directly linking cytokine signaling to cytoskeletal remodeling and contractile function.\",\n      \"evidence\": \"Cell-type-specific IL-17R/Act1 deletion in airway smooth muscle; Co-IP of Rab35/DennD1C with IL-17R/Act1 complex; Rab35 KD, PKCα inhibitor, stress fiber imaging\",\n      \"pmids\": [\"30683702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this cytoskeletal pathway operates in non-smooth-muscle cell types is unknown\", \"Direct kinase-substrate relationship between PKCα and fascin at Ser39 not demonstrated in this IL-17 context by in vitro kinase assay\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Conditional deletion of IL-17RA in intestinal epithelium revealed its role in maintaining microbiome homeostasis and preventing bacterial product translocation, and separately showed fibroblast-specific IL-17RA/STAT3 is required for vaccine-elicited pulmonary immunity.\",\n      \"evidence\": \"Intestinal epithelium-specific and fibroblast-specific IL-17RA conditional KO mice in hepatitis, C. rodentium infection, and Klebsiella vaccine models\",\n      \"pmids\": [\"31747600\", \"34516780\", \"33431657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IL-17RA regulates hydrogen peroxide production mechanistically is not resolved\", \"Whether fibroblast IL-17RA/STAT3 axis operates in non-pulmonary mucosal tissues unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Crystal structures of IL-17RC–IL-17F and IL-17RA–IL-17RC–IL-17A complexes revealed the hexameric signalosome architecture and showed that IL-17RA dimerization is functionally required for downstream gene expression.\",\n      \"evidence\": \"X-ray crystallography of extracellular domains; IL-17RA dimerization-defective mutant with keratinocyte gene expression assays\",\n      \"pmids\": [\"32187518\", \"36260993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length receptor complex structure including intracellular domains not determined\", \"How hexameric assembly propagates signal across the membrane to recruit Act1 is structurally unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that IL-17RA in Lgr5+ intestinal stem cells induces ATOH1 to commit secretory cell lineages revealed a regenerative, non-inflammatory function of IL-17RA in tissue homeostasis.\",\n      \"evidence\": \"Multiple conditional deletions (Lgr5-Cre, ATOH1-Cre), intestinal injury models, human organoid IL-17A stimulation\",\n      \"pmids\": [\"35081371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates between IL-17RA and ATOH1 transcriptional induction not identified\", \"Whether this pathway is active under homeostatic conditions without injury is unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of IL-17RA-dependent ADAM17-mediated MERTK shedding as the mechanism by which IL-17A impairs macrophage efferocytosis provided a mechanistic link between IL-17 signaling and failed inflammation resolution in arthritis.\",\n      \"evidence\": \"IL-17RA silencing and cyanidin treatment restored efferocytosis; ADAM17 KD phenocopied; adjuvant-induced arthritis model\",\n      \"pmids\": [\"38810305\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; independent replication needed\", \"Whether MERTK shedding by IL-17RA/ADAM17 operates in tissue macrophages beyond the synovium is untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Dual cell-type-specific roles of IL-17RA were delineated in colorectal cancer: suppression of EMT via EGFR/Src restraint in epithelial cells, and enabling Syk-dependent IL-18 release from macrophages for anti-tumor CD8+ T cell immunity.\",\n      \"evidence\": \"Conditional IL-17RA deletion in IECs and macrophages; CRC mouse model; EGFR/Src and dectin-1/Syk pathway analysis\",\n      \"pmids\": [\"40023157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IL-17RA restrains EGFR/Src mechanistically is not fully resolved\", \"Relevance to human CRC not yet demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full-length structural model of the IL-17RA signalosome spanning extracellular hexamer through transmembrane to intracellular SEFIR–Act1–TRAF6 assembly remains undetermined, and cell-type-specific transcriptional programs downstream of the common IL-17RA signal are incompletely mapped.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length receptor complex structure exists\", \"Mechanisms selecting between NF-κB, MAPK, STAT3, and non-canonical (Rab35) pathways in different cell types are unknown\", \"How IL-17RA expression is regulated at the post-transcriptional level (beyond FTO/m6A) is poorly understood\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 9, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 9, 14, 34]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 11, 14, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 9, 22, 35, 37]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [\n      \"IL-17RA/IL-17RC\",\n      \"IL-17RA/IL-17RB\",\n      \"IL-17RA/Act1/TRAF6\"\n    ],\n    \"partners\": [\n      \"IL17RC\",\n      \"IL17RB\",\n      \"TRAF1IP2\",\n      \"TRAF6\",\n      \"PEBP1\",\n      \"RAB35\",\n      \"DENND1C\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}